Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans

Louise D. Zheng, Leah E. Linarelli, Longhua Liu, Sarah S. Wall, Mark H. Greenawald, Richard W. Seidel, Paul A. Estabrooks, Fabio A. Almeida, Zhiyong Cheng

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Background: Mitochondrial alterations have been observed in subjects with metabolic disorders such as obesity and diabetes. Studies on animal models and cell cultures suggest aberrant glucose and lipid levels, and impaired insulin signaling might lead to mitochondrial changes. However, the molecular mechanism underlying mitochondrial aberrance remains largely unexplored in human subjects. Results: Here we show that the mitochondrial DNA copy number (mtDNAn) was significantly reduced (6.9-fold lower, p < 0.001) in the leukocytes from obese humans (BMI >30). The reduction of mtDNAn was strongly associated with insulin resistance (HOMA-IR: −0.703, p < 0.05; fasting insulin level: −0.015, p < 0.05); by contrast, the correlation between fasting glucose or lipid levels and mtDNAn was not significant. Epigenetic study of the displacement loop (D-loop) region of mitochondrial genome, which controls the replication and transcription of the mitochondrial DNA as well as organization of the mitochondrial nucleoid, revealed a dramatic increase of DNA methylation in obese (5.2-fold higher vs. lean subjects, p < 0.05) and insulin-resistant (4.6-fold higher vs. insulin-sensitive subjects, p < 0.05) individuals. Conclusions: The reduction of mtDNAn in obese human subjects is associated with insulin resistance and may arise from increased D-loop methylation, suggesting an insulin signaling-epigenetic-genetic axis in mitochondrial regulation.

Original languageEnglish (US)
Article number60
JournalClinical Epigenetics
Volume7
Issue number1
DOIs
StatePublished - Jun 10 2015

Keywords

  • D-loop
  • DNA methylation
  • Epigenetic
  • Genetic
  • Insulin resistance
  • Metabolism
  • Mitochondrial regulation
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

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